New Mathematical Model To Study Disease Genetics And Evolution

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Scientist Develops New Mathematical Model To Study Disease Genetics

And Evolution

http://www.sciencedaily.com/releases/2007/03/070319114440.htm

USC College computational biologist Calabrese has developed a

new model to simulate the evolution of so-called recombination

hotspots in the genome.

Published March 5 in the early online edition of the Proceedings of

the National Academy of Sciences, the mathematical model and its

associated software bring much-needed rigor to evolutionary

investigations of how natural selection acts on individual genes,

said Calabrese, a research assistant professor of biological

sciences.

And, they may also aid the search for disease-associated genes

within the human genome.

The new tools " are more rigorous and less time-consuming than

previous, simpler models, " Calabrese said.

Recent interest in genetic recombination hotspots has been fueled

partly by the promise of genome association studies, which aim to

locate the chromosomal regions responsible for genetic diseases.

Analyzing such studies to understand the inheritance of genes

associated with disease requires an understanding of genetic

recombination at a very fine scale.

Genes are packaged in larger structures called chromosomes. Humans

have 23 pairs of matching chromosomes, one inherited from each

parent. In almost every cell in the body, the maternal and paternal

chromosomes stay separated in these pairs. But the sex cells (sperm

and egg) each carry only one copy of each chromosome, a mix of the

two inherited chromosomes produced by genetic recombination.

During the creation of new sperm or egg cells, paired chromosomes

line up and exchange stretches of DNA before dividing into four

cells, each with its own singular and completely new chromosome,

which will be passed on to offspring.

This genetic re-arrangement and re-shuffling is a major source of

genetic diversity, and so is considered the primary benefit of

sexual reproduction. It's the biological process that makes each

individual (save identical twins) unique, even from close relatives

such as siblings.

To the surprise of many, recent research indicates that most

recombination occurs in small regions of the genome called hotspots.

As scientists have explored details of this process, it's become

clear that the majority -- approximately 80 percent -- of

recombination occurs at these narrow bands of activity, only 1,000

to 2,000 DNA bases wide. Hotspots make up only 10 to 20 percent of

the human genome, which runs about 3 billion DNA bases long. Rates

of recombination at a hotspot may be as much as hundreds to

thousands of times that of the surrounding gene sequence. Little is

known about hotspot origins or how they work.

Scientists have identified a small number of human recombination

hotspots over the last few years. An important advance came in 2005,

when an Oxford University team estimated the location of

approximately 25,000 potential hotspots on the human genome. In

doing so, they assumed the locations of hotspots would not differ

greatly between individuals.

However, comparisons of large numbers of human genomic data

(including the International HapMap Project, which created rough

maps of the genomes of hundreds of people from all around the globe)

have revealed a much more complex picture of hotspots across the

human population. And, work by geneticist Norman Arnheim, a USC

Distinguished Professor and the Ester Dornsife Chair in Biological

Sciences in the College, and others shows that hotspots, like genes

themselves, do vary across the population.

Arnheim, one of Calabrese's collaborators, runs one of a handful of

laboratories in the world that uses the painstaking but powerful

method of sperm typing to study genetic recombination. He and others

have shown that some hotspots are heterogeneous -- not everyone has

the same the hotspots at the same locations.

Calabrese's model and software take these differences, as well as

the chance that the rate of recombination might not be constant over

time, into account, where older models did not.

His work helps explain a number of puzzles confronting those who

study hotspots.

The first is that while chimpanzees, our closest primate relative,

share 99 percent of their genetic code with humans, studies have

revealed almost no overlap in hotspots in their genome.

" The chimp-human comparison really was a surprise, " Calabrese

said. " Even with a very similar DNA sequence, the chimps' hotspots

appear completely independent of humans. "

Calabrese's model fits with and helps to explain this finding. Since

the last common ancestor of chimpanzees and humans lived 6 to 7

million years ago, the model predicts that enough time has passed

for humans to evolve a distinct set of hotspots.

The model also fits with human evidence. Data from the HapMap

project, for example, shows that African-Americans and Asian-

Americans have differences in the locations and frequency of genomic

hotspots, findings backed up by other studies in a number of ethnic

groups. But they also share many hotspots.

Only about 100,000 years have passed since the last major human

migration out of Africa, Calabrese writes in his paper, which his

model predicts is not enough time for geographically separated

populations to have evolved completely unique sets of hotspots.

To Calabrese, one of the most exciting applications of his model is

how it might inform the discussion of the " hotspot paradox. "

A confusing aspect of hotspot origination, the paradox considers how

hotspot locations are tagged. Previously, researchers identified at

least one short sequence of DNA bases, called a DNA motif,

associated with about 10 percent of hotspots in humans. The paradox

arises from the idea that if the " tag " or motif lies too close to

the hotspot, the tag is likely to be lost within a few generations

due to the high rate of DNA breakage at and near the site.

" Obviously, something other than the sequence itself probably codes

for these hotspots, " he said. Another hypothesis is that the DNA

motif is located a good distance away from the hotspot.

Calabrese's model also considers other types of signaling mechanisms

hotspots might employ, such as epigenetic (for example, molecular

tags attached to the DNA, but not the DNA sequence itself) or

multiple, interacting DNA motifs.

The simulation software allows scientists to compare DNA sequences

to find hotspot patterns in the population, which may be important

to understanding disease or evolution.

His coalescent simulation computer program, available free for

download at Calabrese's Web site, showed that existing simulation

software can reliably detect the most common (present in 50 percent

or more of individuals) hotspots in large human genetic datasets,

but probably miss the majority of rarer (present in less than 10

percent of individuals) hotspot sites.

Elucidating the location of and how recombination hotspots work is

critical to building fundamental understanding of the biological

mechanisms that promote genetic variation, Calabrese notes.

Indirectly, the knowledge also may inform the work of scientists

designing better, faster ways to search for genes thought to play a

role in human disease, he said.

The project was supported by a grant from the National Human Genome

Research Institute's Center for Excellence in Genomic Sciences at

USC.